Faculty Bibliography

Coronary plaque rupture is associated with a systemic inflammatory response. The relationship between baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), a prognostic marker in patients with acute coronary syndromes, and systemic inflammatory mediators in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) is not well described. Of 5,745 STEMI patients treated with primary PCI in the APEX-AMI trial, we evaluated the relationship between baseline NT-proBNP levels and baseline levels of inflammatory markers and markers of myonecrosis in a subset of 772 who were enrolled in a biomarker substudy. Spearman correlations (r (s)) were calculated between baseline NT-proBNP levels and a panel of ten systemic inflammatory biomarkers. Interleukin (IL)-6, a pro-inflammatory cytokine, was significantly positively correlated with NT-proBNP (r (s) = 0.317, P < 0.001). In a sensitivity analysis excluding all heart failure patients, the correlation between baseline IL-6 and NT-proBNP remained significant (n = 651, r (s) = 0.296, P < 0.001). A positive association was also observed with high sensitivity C-reactive protein (r (s) = 0.377, P < 0.001) and there was a weak negative correlation with the anti-inflammatory cytokine IL-10 (r (s) = -0.109, P = 0.003). No other significant correlations were observed among the other testes inflammatory cytokines and chemokines. In STEMI patients undergoing primary PCI, the pro-inflammatory cytokine IL-6 was modestly correlated with baseline NT-proBNP levels. This relationship remained significant in patients without heart failure. This finding is consistent with pre-clinical and clinical research suggesting that systemic inflammation may influence NT-proBNP expression independently of myocardial stretch.

OBJECTIVES: The aim of this study was to address the knowledge gap using the APEX-AMI (Assessment of Pexelizumab in Acute Myocardial Infarction) trial database. We also assessed the association between serious infections and 90-day death or death/myocardial infarction (MI). BACKGROUND: Little is known about the incidence, location, etiological organisms, and outcomes of infection in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. METHODS: We analyzed data from 5,745 STEMI patients enrolled in the APEX-AMI trial. Detailed information on infection was collected for all patients. We described characteristics of patients according to infection and details of infection. Cox proportional hazards models were used to assess 90-day outcomes among patients with and without infections after adjusting for associated clinical variables and with infection as a time-dependent covariate. RESULTS: Overall, 138 patients developed a serious infection (2.4%), most of whom presented with a single-site infection. The median (25th, 75th percentile) time until diagnosis of infection was 3 (1, 6) days. The most commonly identified organism was Staphylococcus aureus, and the main location of infection was the bloodstream. These patients had more comorbidities and lower procedural success at index percutaneous coronary intervention than those without infections. Serious infection was associated with significantly higher rates of 90-day death (adjusted hazard ratio: 5.6; 95% confidence interval: 3.8 to 8.4) and death or MI (adjusted hazard ratio: 4.9; 95% confidence interval: 3.4 to 7.1). CONCLUSIONS: Infections complicating the course of patients with STEMI were uncommon but associated with markedly worse 90-day clinical outcomes. Mechanisms for early identification of these high-risk patients as well as design of strategies to reduce their risk of infection are warranted. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637).

BACKGROUND: The OAT, a randomized study of routine percutaneous coronary intervention or optimal medical therapy (MED) alone for the treatment of a totally occluded infarct-related artery in the subacute phase after myocardial infarction, showed similar rates of death, reinfarction and congestive heart failure (CHF) between study groups. Although most percutaneous coronary intervention patients were treated with bare metal stents (BMS), drug-eluting stents (DES) were also implanted in the latter part of the study. The aim of the study was to conduct an exploratory analysis of long-term outcomes for DES vs. BMS deployment vs. MED in the OAT. METHODS: Patients enrolled after February 2003 (when first DES was implanted) were followed (DES n = 79, BMS n = 393, MED n = 552) up to a maximum of 6 years (mean survivor follow-up 5.1 years). RESULTS: The 6-year occurrence of the composite end point of death, reinfarction and class IV CHF was similar [20.4% of DES, 18.9% of BMS and 18.4% of MED (P = .66)] as were the rates of the components of the primary end point. During the follow-up period, 33.4% of DES, 44.4% of BMS and 48.1% of MED patients, developed angina (P = .037). The rate of revascularization during follow up was 11.3%, 20.5% and 22.5% among these groups, respectively (P = .045). CONCLUSIONS: There is no suggestion of reduced long-term risk of death, reinfarction or class IV CHF with DES usage compared to BMS or medical treatment alone. An association between DES use and freedom from angina and revascularization relative to medical therapy is suggested.

BACKGROUND: The OAT study randomized 2,201 patients with a totally occluded infarct-related artery on days 3 to 28 (>24 hours) after myocardial infarction (MI) to percutaneous coronary intervention (PCI) or medical treatment (MED). There was no difference in the primary end point of death, reinfarction, or heart failure at 2.9 or 6-year mean follow-up. However, in patients randomized to PCI, there was a trend toward a higher rate of reinfarction. METHODS: We analyzed the characteristics and types of reinfarction according to the universal definition. Independent predictors of reinfarction were determined using Cox proportional hazard models with follow-up up to 9 years. RESULTS: There were 169 reinfarctions: 9.4% PCI vs 8.0% MED, hazard ratio 1.31, 95% CI 0.97-1.77, P = .08. Spontaneous reinfarction (type 1) occurred with similar frequency in the groups: 4.9% PCI vs 6.7% MED, hazard ratio 0.78, 95% CI 0.53-1.15, P = .21. Rates of type 2 (secondary) and 3 (sudden death) MI were similar in both groups. There was an increase in type 4a reinfarctions (related to protocol or other PCI) (0.8% PCI vs 0.1% MED, P = .01) and type 4b reinfarctions (stent thrombosis) (2.7% PCI vs 0.6% MED, P < .001). Multivariate predictors of reinfarction were history of PCI before study entry (P = .001), diabetes (P = .005), and absence of new Q waves with the index infarction (P = .01). CONCLUSIONS: There was a trend for reinfarctions to be more frequent with PCI. Opening an occluded infarct-related artery in stable patients with late post-MI may expose them to a risk of subsequent reinfarction related to reocclusion and stent thrombosis.

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic science discoveries to clinical practice, ultimately improving the health of the nation. The Clinical and Translational Science Award (CTSA) sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease-agnostic infrastructure devoted to clinical and translational (C&T) science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support.

Background- Regional differences in the profile and prognosis of non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients treated with medical management after angiography remain uncertain. Methods and Results- Using data from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes (EARLY ACS) trial, we examined regional variations in the use of an in-hospital medical management strategy in NSTE ACS patients who had significant coronary artery disease (CAD) identified during angiography, factors associated with the use of a medical management strategy, and 1-year mortality rates. Of 9406 patients, 8387 (89%) underwent angiography and had significant CAD; thereafter, 1766 (21%) were treated solely with a medical management strategy (range: 18% to 23% across 4 major geographic regions). Factors most strongly associated with a medical management strategy were negative baseline troponin values, prior coronary artery bypass grafting, lower baseline hemoglobin values, and greater number of diseased vessels; region was not a significant factor. One-year mortality was higher among patients treated with a medical management strategy compared with those who underwent revascularization (7.8% versus 3.6%; adjusted hazard ratio, 1.46; 95% CI, 1.21-1.76), with no significant interaction by region (interaction probability value=0.42). Conclusions- Approximately 20% of NSTE ACS patients with significant CAD in an international trial were treated solely with an in-hospital medical management strategy after early angiography, with no regional differences in factors associated with medical management or the risk of 1-year mortality. These findings have important implications for the conduct of future clinical trials, and highlight global similarities in the profile and prognosis of medically managed NSTE ACS patients. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT00089895.

Although opening an occluded infarct-related artery >24 hours after myocardial infarction in stable patients in the Occluded Artery Trial (OAT) did not reduce events over 7 years, there was a suggestion that the effect of treatment might differ by patient age. Baseline characteristics and outcomes by treatment with percutaneous coronary intervention (PCI) versus optimal medical therapy alone were compared by prespecified stratification at age 65 years. A p value <0.01 was prespecified as significant for OAT secondary analyses. The primary outcome was death, myocardial infarction, or New York Heart Association class IV heart failure. Patients aged >65 years (n = 641) were more likely to be female, to be nonsmokers, and to have hypertension, lower estimated glomerular filtration rates, and multivessel disease compared to younger patients (aged </=65 years, n = 1,560) (p <0.001). There was no significant observed interaction between treatment assignment and age for the primary outcome after adjustment (p = 0.10), and there was no difference between PCI and optimal medical therapy observed in either age group. At 7-year follow-up, younger patients tended to have angina more often compared to the older group (hazard ratio 1.21, 99% confidence interval 1.00 to 1.46, p = 0.01). The 7-year composite primary outcome was more common in older patients (p <0.001), and age remained significant after covariate adjustment (hazard ratio 1.42, 99% confidence interval 1.09 to 1.84). The rate of early PCI complications was low in the 2 age groups. The trend toward a differential effect of PCI in the young versus the old for the primary outcome was likely driven by measured and unmeasured confounders and by chance. PCI reduces angina to a similar degree in the young and old. In conclusion, there is no indication for routine PCI to open a persistently occluded infarct-related artery in stable patients after myocardial infarction, regardless of age

BACKGROUND: Long-term follow-up (up to 9 years) from the OAT allows for the examination of sex differences in outcomes and the effect of percutaneous coronary intervention (PCI) in a relatively homogeneous cohort of myocardial infarction (MI) survivors. METHODS: The OAT randomized 484 (22%) women and 1717 men to PCI of the occluded infarct-related artery vs medical therapy alone >24 hours post-MI. There was no benefit of PCI on the composite of death, MI, and class IV heart failure. We analyzed outcomes by sex and investigated for sex-based trial selection bias using a concurrent registry. RESULTS: Women were older and more likely to have left anterior descending infarct-related artery, diabetes and hypertension, history of heart failure, and rales at randomization but were less likely to smoke. The proportion and characteristics of women enrolled in the trial and the registry were similar, including left ventricular ejection fraction and extent of disease. Women had higher rates of the primary composite (hazard ratio [HR] 1.48, P = .0002), death (HR 1.50, P = .001), and heart failure (HR 2.53, P < .0001) but not reinfarction (HR 1.12, P = .57). Female sex was not independently associated with the primary end point or death on multivariate analysis. There was a trend toward independent association of female sex with heart failure (HR 1.66, P = .02). CONCLUSION: Women in OAT had a higher primary end point event rate than did men, mainly driven by heart failure. Female sex was not independently associated with death or MI in this well-defined cohort with comparable extent of coronary artery disease, similar medical therapy, and equivalent left ventricular ejection fraction by sex.